Lactate Dehydrogenase Normalization Research Articles

Normalization of Hemoglobin, Lactate Dehydrogenase, and Fatigue in Patients with Paroxysmal Nocturnal Hemoglobinuria Treated with Pegcetacoplan.

We determined normalization rates for hemoglobin, lactate dehydrogenase (LDH), and fatigue in patients with paroxysmal nocturnal hemoglobinuria (PNH) treated with pegcetacoplan (PEG) in the PEGASUS (NCT03500549) and PRINCE (NCT04085601) phase III trials. Enrolled patients had PNH and hemoglobin <10.5 g/dL despite ≥3 months of eculizumab (ECU) [PEGASUS], or were complement component 5 (C5) inhibitor-naive, receiving supportive care only, with hemoglobin less than the lower limits of normal (LLN) [PRINCE]. Hematologic and fatigue normalization endpoints were hemoglobin greater than or equal to the LLN (females: 12 g/dL; males: 13.6 g/dL) in the absence of transfusion; LDH ≤226U/L in the absence of transfusion; and Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue ≥43.6, the general population norm. Safety was assessed by investigators using standardized terms and definitions for seriousness and severity. Hemoglobin normalization occurred in 34.1% (14/41) of PEG-treated patients at Week 16 (randomized controlled period) in PEGASUS (vs. 0% [0/39] of ECU-treated patients) and in 45.7% (16/35) of PEG-treated patients at Week 26 in PRINCE (vs. 0% [0/18] of supportive care-treated patients). At Week 48 (open-label period) in PEGASUS, 24.4% of PEG-treated patients (PEG-to-PEG) and 30.8% of patients treated with ECU through Week 16 who switched to PEG through Week 48 (ECU-to-PEG) had hemoglobin normalization. Rates of LDH normalization in PEGASUS were 70.7% (PEG-treated patients) and 15.4% (ECU-treated patients) at Week 16, and 56.1% (PEG-to-PEG) and 51.3% (ECU-to-PEG) at Week 48. In PRINCE, 67.5% of PEG-treated patients at Week 26 had normalized LDH concentrations. Rates of FACIT-Fatigue score normalization in PEGASUS were 48.8% and 10.3% in PEG- and ECU-treated patients, respectively, at Week 16, and 34.1% and 51.3% in PEG-to-PEG- and ECU-to-PEG-treated patients, respectively, at Week 48. In PRINCE, 68.6% of PEG-treated patients and 11.1% of supportive care patients had FACIT-Fatigue score normalization at Week 26. PEG was safe and well tolerated. Injection site reactions, mostly mild, were the most common adverse event of special interest in PEG-treated patients in the PEGASUS randomized controlled period (36.6%) and in PRINCE (30.4%). PEG is superior to ECU and supportive care in hemoglobin, LDH, and FACIT-Fatigue score normalization for patients with PNH and persistent anemia despite ≥3 months of treatment with ECU, and in C5 inhibitor-naive patients. The PEGASUS trial (NCT03500549) was registered on 18 August 2018, and the PRINCE trial (NCT04085601) was registered on 11 September 2019.

A Case Report of a Patient with Paroxysmal Nocturnal Hemoglobinuria Treated with Pegcetacoplan Who Underwent Major Surgery

Paroxysmal Nocturnal Hemoglobinuria (PNH) is characterized by intravascular hemolysis, thrombosis and bone marrow failure. The appearance of the anti-C5 monoclonal antibody eculizumab revolutionized the treatment of PNH, controlling hemolysis and the incidence of thrombosis. However, some patients persist with anemia, due in part to extravascular C3-mediated hemolysis. More recently, the anti-C3 monoclonal antibody pegcetacoplan, which blocks the most proximal part of the complement cascade, has been marketed in Europe, achieving improvements in anemia in these patients. However, intercurrent infectious episodes or surgical interventions can trigger a hemolytic flare, so dose adjustments are necessary to prevent their occurrence. There is hardly any published information or established consensus on how to treat these patients. We present this case as an example of a successful treatment of a patient diagnosed with PNH under treatment with pegcetacoplan who has undergone major surgery. A 67 year-old man was diagnosed with aplastic anemia in 1997 and treated with immunosuppression (cyclosporine and oxytosone). In 2000, he presented his first intravascular hemolytic crisis with HPN clone detection. He presented several intravascular hemolytic crises for which he was treated with erythropoiesis-stimulating agents, corticosteroids and transfusions. In 2010, due to deterioration of renal function because of acute hemolysis episode, he started treatment with eculizumab. A reduction in the number of hemolytic crises was observed. However, he required an increase in the dose and frequency of administration of eculizumab due to pharmacokinetic breakthrough hemolysis. After one month of treatment, a positive direct coombs test appeared and presented anemia due to extravascular hemolysis, for which he again required treatment with corticosteroids on specific occasions. For this reason, in December 2022, he started treatment with pegcetacoplan at the usual dose of 1080 mg twice a week subcutaneously (sc). Prior to the start of pegcetacoplan, the patient had hemoglobin levels of 10.3 g/dL, hyperbilirubinemia of 3.2 mg/dL (indirect 2.6 mg/dL), consumed haptoglobin, elevated lactate dehydrogenase (LDH) of 281 U/L and reticulocytosis of 5-6%. Subsequently, since the beginning of pegcetacoplan, he presented clinical improvement, stable hemoglobin (12-13 g/dL) and normalization of reticulocytes, LDH and bilirubin levels. The haptoglobin has remained low until the present time. In June 2023, the patient underwent major surgery consisting of radical prostatectomy due to a benign prostatic hypertrophy. Suspecting that it might provoke a hemolytic crisis due to surgical stress, the dose of pegcetacoplan was increased as recommended by clinical experts to a dose of 1080 mg every 72 hours sc from one week prior to surgery until one week after. The procedure was carried out without incident and without an increase in hemolysis parameters. This is the first case report of a patient with PNH treated with pegcetacoplan undergoing major surgery in Spain. In this patient, the perioperative dose increase was successful in preventing the development of a hemolytic crisis.

MDS-111 Hemoglobin, Lactate Dehydrogenase, and FACIT-Fatigue Normalization in Pegcetacoplan-Treated Patients With Paroxysmal Nocturnal Hemoglobinuria from Two Phase 3 Clinical Trials

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, life-threatening disease involving complement-mediated hemolysis. Pegcetacoplan is the first FDA/EMA-approved C3 complement-inhibitor for adults with PNH. We report hemoglobin, lactate dehydrogenase (LDH), and Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue normalization rates in the phase 3 PEGASUS (NCT03500549) and PRINCE (NCT04085601) studies. The PEGASUS study (2018-2020) randomized patients with hemoglobin levels <10.5 g/dL at screening despite stable eculizumab treatment (≥3-months) 1:1 to pegcetacoplan (n=41) or eculizumab (n=39) for the 16-week randomized controlled period (RCP). Eculizumab-treated patients switched to pegcetacoplan during the open-label period through Week 48. The 26-week PRINCE study (2019-2021) randomized complement-inhibitor naive patients 2:1 to pegcetacoplan (n=35) or control treatment ([n=18] without complement-inhibitors: eculizumab/ravulizumab). Normalization was defined separately as hemoglobin ≥gender lower limit of normal, LDH ≤upper limit of normal, and FACIT-Fatigue scores ≥population norm (43.6). Transfusion recipients (hemoglobin/LDH endpoints only), patients withdrawn or lost to follow-up, or control-escape patients (PRINCE) were considered not normalized. Safety endpoints included incidences of adverse events (AEs). Pegcetacoplan demonstrated rapid treatment effects in both studies; Week 2 hemoglobin normalization rates were 43.9% (PEGASUS, baseline 0%) and 22.9% (PRINCE, baseline 2.9%) and Week 2 LDH normalization rates were 87.8% (PEGASUS, baseline 41.5%) and 51.4% (PRINCE, baseline 0%). At Week 16 (PEGASUS) and Week 26 (PRINCE), higher normalization rates were achieved with pegcetacoplan versus respective comparator treatments in hemoglobin (PEGASUS: 34.1% versus 0%; PRINCE: 45.7% versus 0%), LDH (PEGASUS: 70.7% versus 15.4%; PRINCE: 65.7% versus 0%), and FACIT-Fatigue (PEGASUS: 48.8% versus 10.3%; PRINCE: 60.0% versus 11.1%). Numerically similar results were observed at Week 48 in PEGASUS patients randomized to pegcetacoplan or switched from eculizumab to pegcetacoplan. Common AEs in pegcetacoplan-treated patients were injection site reactions (ISRs), diarrhea, abdominal pain, nasopharyngitis, upper respiratory tract infection, hemolysis, cough, and headache for PEGASUS, and ISRs, hypokalemia, and dizziness for PRINCE. Pegcetacoplan rapidly enables higher rates of hemoglobin and LDH normalization, and improvements in FACIT-Fatigue scores compared to eculizumab and control treatment. This further supports the rapid treatment effect of pegcetacoplan in improving clinical parameters and health-related quality of life with a favorable safety profile.

MDS-112 Normalization of Hematologic and Health-Related Quality of Life Markers in Patients With Paroxysmal Nocturnal Hemoglobinuria Treated With Pegcetacoplan and Baseline Hemoglobin at or Above 10 g/dL

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, life-threatening disease characterized by chronic complement-mediated hemolysis. PNH-associated symptoms include anemia and fatigue, with patients requiring frequent blood transfusions. Pegcetacoplan is an FDA/EMA-approved C3 complement inhibitor for adults with PNH. Evaluate normalization rates of hematologic markers, fatigue, and safety after 16 weeks of pegcetacoplan monotherapy in a subgroup of patients with PNH and baseline hemoglobin levels ≥10.0 g/dL from the PEGASUS (NCT03500549), PADDOCK (NCT02588833), and PRINCE (NCT04085601) studies. PEGASUS (2018-2020) enrolled patients with hemoglobin levels <10.5 g/dL at screening despite stable eculizumab treatment (≥3 months) and randomized patients 1:1 to eculizumab or pegcetacoplan for the 16-week randomized controlled period (RCP). Eculizumab-treated patients in the RCP switched to pegcetacoplan through week 48 for the open-label period. PADDOCK (2015-2019) and PRINCE (2019-2021) evaluated pegcetacoplan in complement inhibitor-naïve patients. PRINCE compared pegcetacoplan to control (excluding eculizumab/ravulizumab) in patients with hemoglobin levels below gender-specific lower limits of normal. This post-hoc analysis included adults with PNH, baseline hemoglobin levels ≥10.0 g/dL, and no transfusions within 14 days of baseline. Hemoglobin, lactate dehydrogenase (LDH), absolute reticulocyte count (ARC), and Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue normalization were evaluated after pegcetacoplan monotherapy for 16 weeks. Patients who withdrew or were lost to follow-up without efficacy data at specified timepoints were considered not normalized. Safety endpoints included incidences of adverse events (AEs). This analysis included 22 patients: 9 PEGASUS, 5 PADDOCK, and 8 PRINCE. Sixteen weeks of pegcetacoplan monotherapy led to increases in hemoglobin (PEGASUS: 66.7%; PADDOCK: 40.0%; PRINCE: 62.5%) and LDH (PEGASUS: 77.8%; PADDOCK: 60.0%; PRINCE: 100.0%) normalization rates, with similar results in ARC and FACIT-Fatigue. No serious AEs were reported in PADDOCK or PRINCE subgroups. One PEGASUS patient had a serious AE (breakthrough hemolysis; severe, unrelated to pegcetacoplan, resolved, no discontinuation) following upper respiratory infection. Injection site reactions and infections/infestations occurred at similar rates among subgroups. No thrombotic events occurred in this subgroup. Results suggest pegcetacoplan can be efficacious in patients with less severe anemia regardless of prior complement inhibitor treatment, further improving clinical markers of hemolysis and fatigue. The safety profile of pegcetacoplan was consistent with previous studies.

P828: NORMALIZATION OF HEMATOLOGIC AND HEALTH-RELATED QUALITY OF LIFE MARKERS IN PATIENTS WITH PAROXYSMAL NOCTURNAL HEMOGLOBINURIA TREATED WITH PEGCETACOPLAN AND BASELINE HEMOGLOBIN AT OR ABOVE 10 G/DL

Background: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare life-threatening disease characterized by chronic complement-mediated hemolysis and thrombosis. Patients living with PNH can experience anemia with associated fatigue, dyspnea, and require blood cell transfusions which can negatively impact quality of life (QoL). Pegcetacoplan (PEG), is a C3 complement-inhibitor approved by the FDA/EMA for adults with PNH. Aims: This post hoc analysis evaluated hemoglobin (Hb), lactate dehydrogenase (LDH), absolute reticulocyte count (ARC), and Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue normalization rates and safety after PEG treatment in a subgroup of patients with PNH and baseline Hb levels ≥10.0g/dL from the PADDOCK (NCT02588833), PEGASUS (NCT03500549), and PRINCE (NCT04085601) studies. Methods: PADDOCK evaluated PEG treatment (270-360mg/day subcutaneously [sc]) in complement-inhibitor naïve patients. PEGASUS enrolled patients with Hb levels <10.5g/dL at screening despite stable eculizumab (ECU) treatment (≥3 months). PEGASUS patients were randomized 1:1 to ECU or PEG (1080mg sc 2x weekly) during the randomized controlled period (RCP) through Week 16. Patients who received PEG during the RCP continued with PEG monotherapy (PEG-to-PEG) and ECU patients switched to PEG monotherapy (ECU-to-PEG) during the open-label period (OLP) through Week 48. PRINCE compared PEG treatment (1080mg sc 2x weekly) in complement-inhibitor naïve patients with PNH and Hb levels below the lower limits of normal (males: ≤13.6g/dL; females: ≤12.0g/dL) to control treatment (CTRL; excluding complement-inhibitors i.e., ECU/ravulizumab). The post hoc analysis included adult patients with PNH with baseline Hb levels ≥10.0g/dL and no transfusions within 14 days of the baseline measurement. Hb, LDH, and ARC normalization, as well as FACIT-Fatigue normalization (defined as increase to population norm) was evaluated after 16 weeks of PEG monotherapy for all three studies. Patients who withdrew or were lost to follow-up without providing efficacy data at the specified timepoints were classified as non-responders. Safety endpoints included incidences of adverse events (AEs). Results: Overall, 22 patients were included in the post hoc analysis: 5 PADDOCK, 9 PEGASUS, and 8 PRINCE patients. After 16 weeks of pegcetacoplan treatment, patients in all three studies showed improvements in Hb normalization, LDH normalization, and ARC normalization (Table 1). Additionally, improvements in FACIT-Fatigue normalization were demonstrated in PADDOCK, PRINCE, and PEGASUS (PEG-to-PEG) patients (Table 1). No incidences of serious AEs were reported in PADDOCK and PRINCE subgroups. One PEGASUS patient had a serious AE of breakthrough hemolysis (severe, unrelated to PEG), following an upper respiratory infection which resolved and did not lead to study discontinuation. Incidences of injection site reactions and infections and infestations occurred at similar rates between subgroups in all three studies (Table 1). No thrombotic events occurred in this patient population. Image:Summary/Conclusion: While this patient population had near normal Hb at baseline (median: 10.4g/dL), they also had elevated ARC and LDH prior to PEG therapy, suggesting ongoing hemolysis which was normalized in most patients after PEG treatment initiation. Overall, these results suggest PEG can be efficacious long-term in patients with less severe anemia, regardless of prior complement-inhibitor treatment, resulting in further clinical improvements in markers of hemolysis and QoL. The safety profile of PEG was consistent with results from previous studies.

P840: A MATCHING-ADJUSTED INDIRECT COMPARISON OF THE EFFICACY OF PEGCETACOPLAN USING PRINCE TRIAL DATA VERSUS RAVULIZUMAB AND ECULIZUMAB IN COMPLEMENT-NAÏVE PATIENTS WITH PAROXYSMAL NOCTURNAL HEMOGLOBINURIA

Background: Pegcetacoplan (PEG) is a PEGylated peptide targeting proximal complement protein C3 that has been shown to control both intravascular and extravascular hemolysis and recently approved by the FDA and EMA for the treatment of paroxysmal nocturnal hemoglobinuria (PNH). PRINCE (NCT04085601), was a phase-3, randomized, open-label trial assessing the efficacy and safety of PEG compared to control (CTL) treatment, excluding complement inhibitors among treatment naïve patients with PNH. PEG demonstrated superior efficacy to CTL by improving hemoglobin (Hb) levels and reductions in lactate dehydrogenase (LDH) levels in patients with PNH. To date, no head-to-head clinical trials exist comparing PEG to complement inhibitors in treatment naïve patients. Aims: To assess the comparative effectiveness of PEG for complement-naïve patients with PNH against ravulizumab (RAV) and eculizumab (ECU) using matching-adjusted indirect comparison (MAIC) methodology to conduct cross-trial comparisons. Methods: Individual patient data from PRINCE as well as aggregated published results of RAV and ECU in the ALXN1210-PNH-301 (“301”) study (Lee et al. 2019) were used. To adjust for cross-study differences, propensity score weighting was developed using logistic regression analyses and used to balance demographic and clinical characteristics between the PEG arm and RAV and ECU arms from 301. Outcomes were compared at 26 weeks using unanchored MAIC between PEG versus RAV and PEG versus ECU and included mean and percent change in LDH levels from baseline, LDH normalization (defined as LDH levels dropping <1xULN [246 U/L] in the absence of transfusions during the randomized controlled period), Hb stabilization (defined as the avoidance of a ≥2 g/dL decrease in hemoglobin level in the absence of transfusions during the randomized controlled period), and transfusion avoidance. Weighted Wald tests and 95% confidence intervals were computed for comparisons of categorical and continuous outcomes. Results: A total of 34 patients were included in the PEG arm, 125 patients in the RAV arm, and 121 patients in the ECU arm. Prior to matching, significant differences existed between arms in the proportion of patients with White and American Indian or Alaska Native race, and mean LDH (all p<0.001). After matching the PEG to the RAV and ECU arms, separately, most patient characteristics were well balanced with a mean age of 43.8 years, 44.8 years, 46.2 years, respectively, 43.0-50.0% females, and a mean Hb of 9.4-9.6g/dL across arms; however, there were significant differences in Asian race and baseline LDH (all p<0.01). At week 26, patients in the PEG arm showed a significantly greater improvement in their LDH levels from baseline, with a mean of -523 U/L (-11.2%) compared to RAV and -578 U/L (-12.0%) compared to ECU (all p<0.001; Figure 1). Patients receiving PEG also showed significant improvements in LDH normalization (35.6% compared to RAV, p<0.001; 39.6% compared to ECU, p<0.001), Hb stabilization (28.2% compared to RAV, p<0.001; 31.7% compared to ECU, p<0.001), and transfusion avoidance (22.6% compared to RAV, p<0.001; 30.1% compared to ECU, p<0.001; Figure 1). Image:Summary/Conclusion: In the absence of head-to-head comparisons, this unanchored MAIC study shows that PEG is more efficacious versus RAV and ECU in complement inhibitors treatment naïve PNH patients in terms of significant improvements across all evaluated endpoints, Hb stabilization, LDH improvement, LDH normalization and transfusion avoidance.

Real World Use of Narsoplimab in a Case of Severe HSCT-TMA

Introduction: Hematopoietic stem cell transplantation (HSCT) offers a curative approach for hematologic malignancies. However, endothelial injury from HSCT activates the lectin pathway of complement, resulting in complications such as thrombotic microangiopathy (TMA). HSCT-TMA causes significant mortality. Incidence is reported up to 39%, although lack of consensus on diagnostic criteria results in under-recognition. Risk factors for HSCT-TMA include calcineurin inhibitors (CNI), conditioning, and infection. There is currently no approved treatment for HSCT-TMA.Narsoplimab is a monoclonal antibody that inhibits MASP-2, the effector enzyme of the lectin pathway. We report a patient with late-onset HSCT-TMA who was successfully treated with narsoplimab via a compassionate use program.Methods and Results: A 60-year-old woman with de novo acute myeloid leukemia t (9;11) (p22; q23) who achieved first complete remission (CR1) with minimal residual disease positivity confirmed by flow cytometry (0.04%) underwent matched related allogeneic HSCT from her sister. Patient was cytomegalovirus (CMV) seropositive and blood group O, whereas donor was CMV seronegative and blood group B. Patient received induction with 7+3 and HiDAC consolidation, achieving CR1. Conditioning regimen was Bu4Flu with graft versus host disease (GVHD) prophylaxis of mini methotrexate and tacrolimus.Letermovir was used for CMV reactivation prophylaxis until Day +100. Post-transplant maintenance therapy with azacitidine 36 mg/m 2 was administered by four 5-day cycles (de Lima Cancer 2010). Patient achieved completed donor myeloid CD33 chimerism at Day +30, but donor lymphoid CD3 chimerism was not complete until Day +239. Tacrolimus was discontinued at Day +180. Patient initially had red cell aplasia but achieved transfusion independence by 6 months post-transplant.Circa achieving complete donor CD3 chimerism, patient developed extensive skin and gastrointestinal-overlap GVHD requiring admission for high-dose steroid therapy and resumption of tacrolimus. Onset of GVHD precluded stopping CNI. Patient became steroid refractory and ruxolitinib was added for immunosuppression with resolution of symptoms.Four weeks later, patient developed CMV reactivation and started induction therapy with valganciclovir, during which time she became red cell-transfusion dependent. Patient required 3 weeks induction and 10 days maintenance to clear CMV viremia.Subsequently, she reported dark red urine with evidence for hemoglobinuria without viruria, bilateral leg edema unresponsive to diuretic therapy, and rising serum lactate dehydrogenase (LDH). Evaluation revealed negative direct antiglobulin test, schistocytes on peripheral blood smear (~5/hpf), elevated sC5b-9 levels of 334 ng/mL (72-244 ng/mL), and elevated random urine protein of 124 mg/dL indicative of end organ damage. LDH was modestly elevated 302 IU/L (84-246 IU/L) and haptoglobin was elevated. Based on clinical symptoms and lab results, she was diagnosed with late-onset HSCT-TMA on Day +282 (9 months) using published diagnostic criteria proposed by Cho (2010) and Jodele (2014).The patient's clinical symptoms worsened with severe leg edema - which impeded her ability to walk - and red cell and platelet transfusion dependency. With no approved therapies, compassionate use of narsoplimab was requested for this clinical course of HSCT-TMA. Treatment commenced on Day +309.Patient received a total of 21 doses of narsoplimab 370 mg administered twice weekly on an outpatient basis. All infusions were well tolerated. No adverse events were noted with narsoplimab. Peripheral counts, LDH, anemia, thrombocytopenia and sC5b-9 normalized with reduction in proteinuria, reflecting resolution of HSCT-TMA by dose 19 (10 weeks of treatment); two additional doses were administered (Figure 1). Narsoplimab was given concomitantly with tacrolimus. Patient became transfusion independent and leg edema resolved.Conclusions: This report presents a real-world case study of HSCT-TMA treated with narsoplimab via compassionate use. HSCT-TMA resolved after 10 weeks of treatment, as evidenced by peripheral counts, normalization of LDH and sC5b-9, reduction in urinary protein reflecting improvement in renal function, and improvement in clinical symptoms. Narsoplimab was effective in this complicated case despite several risk factors for poor outcomes. [Display omitted] DisclosuresPantin: Omeros Corporation: Honoraria. Billy: Omeros Corporation: Current Employment. OffLabel Disclosure:Off-label use of azacitidine for post-transplant maintenance therapy

Optimization of Dose Regimen for ALXN1210, a Novel Complement C5 Inhibitor, in Patients with Paroxysmal Nocturnal Hemoglobinuria (PNH): Results of 2 Phase 1/2 Studies

Optimization of Dose Regimen for ALXN1210, a Novel Complement C5 Inhibitor, in Patients with Paroxysmal Nocturnal Hemoglobinuria (PNH): Results of 2 Phase 1/2 Studies

Prognostic factors and follow-up parameters in patients with paroxysmal nocturnal hemoglobinuria (PNH): experience of the Austrian PNH network.

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare hematologic disease characterized by a deregulated complement system, chronic Coombs-negative, intravascular hemolysis, and a variable clinical course with substantial risk to develop thromboembolic events. We analyzed diagnostic and prognostic parameters as well as clinical endpoints in 59 adult patients suffering from PNH in 5 hematology centers in Austria (observation period: 1978-2015). Median follow-up time was 5.6 years. The median clone size at diagnosis amounted to 55% and was higher in patients with classical PNH (81%) compared to patients with PNH associated with aplastic anemia (AA) or myelodysplastic syndromes (MDS) (50%). The clone size also correlated with lactate dehydrogenase (LDH) levels. In one patient, anemia improved spontaneously and disappeared with complete normalization of LDH after 16 years. Seventeen patients received therapy with eculizumab. The rate of thromboembolic events was higher in the pre-eculizumab era compared with eculizumab-treated patients but did not correlate with the presence of age-related clonal hematopoiesis or any other clinical or laboratory parameters. Peripheral blood colony-forming progenitor cell counts were lower in PNH patients compared with healthy controls. Only two patients with classical PNH developed MDS. Overall, 7/59 patients died after 0.5-32 years. Causes of death were acute pulmonary hypertension, Budd-Chiari syndrome, and septicemia. Overall survival (OS) was mainly influenced by age and was similar to OS measured in an age-matched healthy Austrian control cohort. Together, compared with previous times, the clinical course and OS in PNH are favorable, which may be due to better diagnosis, early recognition, and eculizumab therapy.

Clinical evaluation of potential usefulness of serum lactate dehydrogenase (LDH) in 2019 novel coronavirus (COVID-19) pneumonia

BackgroundThere was much evidence suggesting that the serum lactate dehydrogenase (LDH) levels reflect the extent of various pathophysiological processes. However, the current information about dynamic change of LDH in COVID-19 pneumonia has not been well investigated.MethodsStudy was performed in 87 cases confirmed by COVID-19 infection. The serum LDH levels were determined at diagnosis and follow-up visits. The evaluation of clinical response to therapy was based on chest CT scan. We selected the value of LDH around the data of chest CT scan (− 1 ~ + 1 day).ResultsAt diagnosis, significant differences in LDH levels were found between non-severe and severe group (P < 0.05). It was demonstrated that increase or decrease of LDH was indicative of radiographic progress or improvement (P < 0.05). The time to LDH normalization (5.67 ± 0.55, days) was positively correlated with the time to radiographic absorption (5.57 ± 0.65 days, r = 0.53, P < 0.05). Applying the cut-off value of the increase in LDH has good specificity to predict disease progression.ConclusionsSerum LDH was validated for its potential usefulness as markers for evaluating clinical severity and monitoring treatment response in COVID-19 pneumonia.

One-year efficacy and safety of ravulizumab in adults with paroxysmal nocturnal hemoglobinuria naïve to complement inhibitor therapy: open-label extension of a randomized study.

Background:Ravulizumab, the only long-acting complement C5 inhibitor for adults with paroxysmal nocturnal hemoglobinuria (PNH), demonstrated non-inferiority to eculizumab after 26 weeks of treatment in complement inhibitor-naïve patients during a phase III randomized controlled trial. We present open-label extension results with up to 52 weeks of treatment.Methods:Patients assigned to ravulizumab every 8 weeks (q8w) or eculizumab every 2 weeks during the randomized primary evaluation period received ravulizumab q8w during the 26-week extension. Efficacy endpoints were lactate dehydrogenase (LDH) normalization, transfusion avoidance, breakthrough hemolysis (BTH), LDH levels, Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue scale, and stabilized hemoglobin. Serum free C5 levels and safety were assessed. Outcomes as of the data cut-off (4 September 2018) were summarized using descriptive statistics.Results:Overall, 124 patients continued ravulizumab, and 119 switched from eculizumab to ravulizumab. During the extension, 43.5% and 40.3% of patients in the ravulizumab–ravulizumab and eculizumab–ravulizumab arms, respectively, achieved LDH normalization; 76.6% and 67.2% avoided transfusion. BTH decreased in the eculizumab–ravulizumab arm; no events were associated with free C5 ⩾0.5 μg/mL while receiving ravulizumab. Overall, 73.4% and 65.5% of patients in the ravulizumab–ravulizumab and eculizumab–ravulizumab arms, respectively, achieved stabilized hemoglobin. Similar proportions of patients achieved ⩾3-point improvement in FACIT-Fatigue at week 52 (ravulizumab–ravulizumab, 64.5%; eculizumab–ravulizumab, 57.1%). All patients maintained free C5 <0.5 μg/mL during the ravulizumab extension, including those who experienced C5 excursions ⩾0.5 μg/mL while receiving eculizumab during the primary evaluation period. Adverse events were comparable between groups and decreased over time.Conclusion:In adult, complement inhibitor–naïve patients with PNH, ravulizumab q8w for up to 52 weeks demonstrated durable efficacy and was well tolerated, with complete and sustained free C5 inhibition and a decreased incidence of BTH with no events associated with loss of free C5 control.Trial registration:ClinicalTrials.gov identifier, NCT02946463

Switching to Immune Checkpoint Inhibitors upon Response to Targeted Therapy; The Road to Long-Term Survival in Advanced Melanoma Patients with Highly Elevated Serum LDH?

The prognosis of patients with advanced melanoma has improved dramatically. However, the clinical outcomes of patients with highly elevated serum lactate dehydrogenase (LDH) remain very poor. The aim of this study was to explore whether patients with normalized LDH after targeted therapy could benefit from subsequent treatment with immune checkpoint inhibitors (ICI). Data from all patients with BRAF-mutant metastatic melanoma with a highly elevated serum LDH at baseline (≥2× upper limit of normal) receiving first-line targeted therapy between 2012 and 2019 in the Netherlands were collected. Patients were stratified according to response status to targeted therapy and change in LDH at start of subsequent treatment with ICI. Differences in overall survival (OS) between the subgroups were compared using log-rank tests. After a median follow-up of 35.1 months, median OS of the total study population (n = 360) was 4.9 months (95% CI 4.4–5.4). Of all patients receiving subsequent treatment with ICI (n = 113), survival from start of subsequent treatment was significantly longer in patients who had normalized LDH and were still responding to targeted therapy compared to those with LDH that remained elevated (median OS 24.7 vs. 1.1 months). Our study suggests that introducing ICI upon response to targeted therapy with normalization of LDH could be an effective strategy in obtaining long-term survival in advanced melanoma patients with initial highly elevated serum LDH.

Study Design of an Open-Label, Single-Arm, Multicenter, Phase 2 Study to Evaluate the Safety and Efficacy of Defibrotide in Adult Patients with Transplant-Associated Thrombotic Microangiopathy

Background: Transplant-associated thrombotic microangiopathy (TA-TMA) is an uncommon, but well-recognized, hematopoietic cell transplant (HCT) complication associated with high morbidity and mortality. TA-TMA may result from microvascular endothelial cell (EC) damage induced by HCT conditioning regimens, immunosuppressive drugs, and infections, and it may be mediated by complement activation in some cases. Although there is no consensus on optimal TA-TMA treatment, common interventions include withdrawal, replacement, or dose modification of calcineurin inhibitors (CI) and/or mammalian target of rapamycin (mTOR) inhibitors (ie, CI/mTORi changes). When increased complement activity is present, terminal complement cascade inhibition has been used. Defibrotide (DF) is approved for adult and pediatric patients (pts) with hepatic veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) with renal or pulmonary dysfunction post-HCT in the US and Canada and for pts aged &gt;1 month with severe hepatic VOD/SOS post-HCT in the EU. DF reduces EC activation, promotes fibrinolysis, and may be a novel therapy for TA-TMA. This prospective, open-label, single-arm, multicenter, phase 2 study (EUDRACT: 2018-001101-90) is designed to assess the efficacy and safety of DF for treating pts with high-risk TA-TMA (defined as definite TMA per Postalcioglu M, et al. Biol Blood Marrow Transplant. 2018;24(11):2344-2353) who have failed to respond to CR/mTORi changes. Study Design and Methods: Diagnostic criteria for "definite" TA-TMA include lactate dehydrogenase (LDH) &gt;2 × the upper limit of normal, thrombocytopenia (platelet count &lt;50 × 109/L or ≥50% decrease from peak platelets post-HCT), schistocytes ≥2 per high-power field in peripheral blood, serum creatinine increase &gt;50% from baseline, and a negative Coombs test. Allogeneic HCT pts (aged ≥18 years) who have definite TA-TMA with persistent or progressive disease after 7 or 3 days, respectively, following CI/mTORi changes are eligible (Figure). Pts will be excluded if they relapse after HCT, have grade 4 acute graft-versus-host disease or VOD/SOS, or clinically significant bleeding within 24 hours of enrollment. Planned enrollment is 30 to 40 pts. Pts will receive a 2-hour intravenous infusion of DF 25 mg/kg/day (6.25 mg/kg every 6 hours) for a recommended duration of 21 days (up to 60 days). Pts will be followed for 180 days from DF start (Day 1). The study has 2 co-primary efficacy endpoints: hematologic response by Day 45 (relative to DF start) and renal response by Day 45. Hematologic response is defined as normalization of LDH and platelet count ≥50 × 109/L without platelet transfusion for 7 days (if baseline count was &lt;50 × 109/L) or ≥50% increase in platelet count (if baseline count was ≥50 × 109/L). Renal response is defined as &lt;25% increase or decrease in serum creatinine versus baseline at DF start (renal function stabilization) or ≥25% decrease in serum creatinine versus baseline at DF start or independence from dialysis (if pt was dialysis dependent at baseline or started dialysis after baseline) (renal function improvement). Secondary efficacy endpoints are overall survival, duration of hematologic or renal response, proportion of pts achieving hematologic or renal (measured by serum creatinine or estimated glomerular filtration rate) response by Days 60, 90, and 180, independence from dialysis at Days 60, 90, and 180 for pts with dialysis dependence, and neurologic improvement (defined as any increase in Mini-Mental Status Examination score versus baseline or resolution of TA-TMA seizure activity) at Days 7, 14, 21, and 45. Safety endpoints include incidence of treatment-emergent adverse events (AEs), treatment-emergent serious AEs, and AEs of interest (eg, hemorrhage and hypotension) occurring up to 30 days after the last DF dose. Analysis of the co-primary efficacy endpoints will be evaluated in pts who receive ≥1 DF dose. For each co-primary endpoint, a reference background rate, based upon data from literature and/or registries or research databases, will be established to represent the Day 45 hematologic and renal response rates in a similar pt population in the setting of currently available therapy without DF treatment. A clinically meaningful benefit from DF will be inferred if the lower bounds of the 95% confidence interval of the co-primary endpoints are greater than their respective reference background rates. Disclosures Ho: Jazz Pharmaceuticals: Consultancy. Keshelava:Jazz Pharmaceuticals: Employment, Equity Ownership. Swann:Jazz Pharmaceuticals: Employment, Equity Ownership. Tappe:Jazz Pharmaceuticals: Employment, Equity Ownership. OffLabel Disclosure: The abstract contains a description of off-label product use. Defibrotide is approved for treatment of hepatic VOD/SOS post-HCT (as described in the background) and this study is evaluating its use in patients with TA-TMA.

Comparative and Interactive Biochemical Effects of Sub-Lethal Concentrations of Cadmium and Lead on Some Tissues of the African Catfish (Clarias gariepinus)

Cadmium is a strong toxic heavy metal which presents in paints and liquid wastes and causes oxidative stress in fish. On the other hand, lead is widely used for different purposes, e.g. lead pipes, it targets vital organs such as liver and kidney causing biochemical alterations. The present study evaluates the effects of 60 days exposure to Cd and Pb either single or combined together in African catfish. Sixty-four fishes were divided into 3 groups and exposed to CdCl2 (7.02 mg/L) or PbCl2 (69.3 mg/L) or a combination of them along with control group. Activities of acid phosphatase (ACP), lactate dehydrogenase (LDH) and glucose-6-phosphate dehydrogenase (G-6-PDH) were estimated. Moreover, gill, liver and kidney were assayed for activities of superoxide dismutase (SOD), catalase (CAT) and levels of glutathione (GSH) and malondialdehyde (MDA). Individual exposure showed that both Cd and Pb significantly decreased LDH activity and SOD activity in the kidney. Pb significantly increased G-6-PDH activity and decreased GSH level in the gill. CAT activity in liver and kidney elevated significantly on Cd exposure while lead caused a significant depletion in the liver and significant elevation in the kidney. Both Cd and Pb significantly increased MDA levels in liver and kidney while Pb increased its level in gills. The combined exposure resulted in normalization of LDH, G-6-PDH activity, and CAT activity in liver and kidney as well as GSH level in both tissues and MDA in gill and kidney. The combination increased SOD activity and MDA level in liver and decreased SOD activity in kidney and GSH level in gills. In conclusion, the antioxidant system of African catfish was adversely affected by prolonged exposure to Cd and Pb. The combined exposure caused less damage than individual exposure and returned most parameters to those of controls.

S864 A PHASE 2 OPEN-LABEL PROOF OF CONCEPT STUDY OF THE ORAL, SMALL MOLECULE FACTOR D INHIBITOR, ACH-4471, IN UNTREATED PATIENTS WITH PAROXYSMAL NOCTURNAL HEMOGLOBINURIA (PNH)

Background: Ravulizumab, a novel C5 complement inhibitor, was approved by FDA for treating paroxysmal nocturnal hemoglobinuria (PNH) and is under review in EMEA and Japan. In the largest phase 3 study in complement inhibitor-naive PNH patients (pts) conducted to date, qw8 ravulizumab was noninferior to qw2 eculizumab for all primary and secondary endpoints after 26 wks. To evaluate long-term efficacy and safety, all pts had the option of continuing to receive ravulizumab in an extension study. Aims: To characterize the durability of efficacy responses to ravulizumab through 52 wks and to evaluate the efficacy profile of ravulizumab after switching from eculizumab in adult PNH pts naive to eculizumab therapy (NCT02946463). Methods: This phase 3, randomized, active-controlled, open-label study was conducted in 123 centers in 25 countries. Pts were randomly assigned to receive eculizumab (n = 121) or ravulizumab (n = 125) for 26 wks, after which pts in the ravulizumab arm continued ravulizumab maintenance therapy (R-R arm), while pts in the eculizumab arm were then switched to ravulizumab (E-R arm). Results of the co-primary [lactate dehydrogenase normalization (LDH-N), transfusion avoidance] and key secondary endpoints [breakthrough hemolysis (BTH) and LDH levels] are provided descriptively. Plasma free C5 levels were obtained through 52 wks. Results: During the first 26 wks, 74% of pts in the R-R arm avoided transfusion, compared to 77% avoiding transfusion in wks 27–52. More than 90% (n = 83) of pts who avoided transfusion during the initial 26 wk period maintained this response through 52 wks, and 38% (n = 12) who required transfusion in the 0–26 wk period avoided it in wks 27–52. In the E-R arm, 66% (26 wks) vs 67% (52 wks) avoided transfusion; 87% (n = 69) who avoided transfusion for 26 wks maintained this response through 52 wks. Additionally, 28% (n = 11) who required transfusion during the 26 wks while on eculizumab avoided it through 52 wks once switched to ravulizumab. In the R-R arm, LDH-N occurred in 48% of pts (n = 60) at 26 wks and in 44% of pts (n = 54) at 52 wks. Similarly, in the E-R arm, at 26 wks, LDH-N was 42%, and was 40% at 52 wks. At the end of 26 wks, pts on ravulizumab had a 77% (SEM = 1.4) mean reduction in LDH from baseline and this was maintained through 52 wks (77%, SEM = 1.2). All pts (n = 119) in the ravulizumab treatment group continued to maintain free C5 <0.5 μg/mL at all time points through 52 wks (Figure). In pts initially randomized to eculizumab, the switch to ravulizumab showed improved free C5 control, and no patients had free C5 >0.5 μg/ml after the switch. Of the 125 pts initially on ravulizumab, 5 pts (4%) had BTH in the first 26 wks vs 4 pts (3%) during wks 27–52. In the E-R arm, 13 pts (11%) experienced BTH during the first 26 wks vs 2 pts (2%) in wks 27–52 after the switch to ravulizumab. During wks 27–52, none of the BTH events in both arms were associated with free C5 >0.5 μg/ml, the threshold associated with complete inhibition of hemolysis. These results demonstrate maintenance of complete free C5 control in pts receiving ravulizumab. Ravulizumab was well tolerated and the most common treatment-related adverse events decreased in frequency with increased treatment duration.Summary/Conclusion: Ravulizumab demonstrated consistent and durable efficacy over 52 wks of treatment. Importantly, all pts who had suboptimal free C5 control receiving eculizumab achieved complete free C5 inhibition after the switch to ravulizumab. Complete suppression of free C5 level was associated with a decreased incidence of BTH.

Ravulizumab (ALXN1210) vs eculizumab in adult patients with PNH naive to complement inhibitors: the 301 study

AbstractRavulizumab (ALXN1210), a new complement C5 inhibitor, provides immediate, complete, and sustained C5 inhibition. This phase 3, open-label study assessed the noninferiority of ravulizumab to eculizumab in complement inhibitor–naive adults with paroxysmal nocturnal hemoglobinuria (PNH). Patients with lactate dehydrogenase (LDH) ≥1.5 times the upper limit of normal and at least 1 PNH symptom were randomized 1:1 to receive ravulizumab or eculizumab for 183 days (N = 246). Coprimary efficacy end points were proportion of patients remaining transfusion-free and LDH normalization. Secondary end points were percent change from baseline in LDH, change from baseline in Functional Assessment of Chronic Illness Therapy (FACIT)–Fatigue score, proportion of patients with breakthrough hemolysis, stabilized hemoglobin, and change in serum free C5. Ravulizumab was noninferior to eculizumab for both coprimary and all key secondary end points (Pinf < .0001): transfusion avoidance (73.6% vs 66.1%; difference of 6.8% [95% confidence interval (CI), −4.66, 18.14]), LDH normalization (53.6% vs 49.4%; odds ratio, 1.19 [0.80, 1.77]), percent reduction in LDH (−76.8% vs −76.0%; difference [95% CI], −0.83% [−5.21, 3.56]), change in FACIT-Fatigue score (7.07 vs 6.40; difference [95% CI], 0.67 [−1.21, 2.55]), breakthrough hemolysis (4.0% vs 10.7%; difference [95% CI], −6.7% [−14.21, 0.18]), and stabilized hemoglobin (68.0% vs 64.5%; difference [95% CI], 2.9 [−8.80, 14.64]). The safety and tolerability of ravulizumab and eculizumab were similar; no meningococcal infections occurred. In conclusion, ravulizumab given every 8 weeks achieved noninferiority compared with eculizumab given every 2 weeks for all efficacy end points, with a similar safety profile. This trial was registered at www.clinicaltrials.gov as #NCT02946463.

A Phase 3 Study of Ravulizumab (ALXN1210) Versus Eculizumab in Adults with Paroxysmal Nocturnal Hemoglobinuria Naive to Complement Inhibitors: Results of a Subgroup Analysis with Patients Stratified By Baseline Hemolysis Level, Transfusion History, and Demographics

Background/Objective: Ravulizumab (ALXN1210) is an innovative C5 inhibitor with high C5 affinity and a half-life approximately 4 times longer than eculizumab. In the largest interventional clinical study of C5 inhibitor-naive patients with paroxysmal nocturnal hemoglobinuria (PNH) to date, ravulizumab administered every 8 weeks (q8w) was shown to be noninferior to eculizumab (every 2 weeks [q2w]) across 2 coprimary endpoints and 4 key secondary endpoints, due to its ability to provide immediate, complete, and sustained inhibition of complement C5 (Lee et al, EHA-2018). Because PNH is a rare disease, prospective evaluation of new agents for the treatment of this disease, with the exception of ravulizumab, has been limited to small populations. As a result, assessing the effect of treatment in patients with unique disease characteristics and gaining a full understanding of the benefit-to-risk profile of new therapies, has been challenging. The objective of this protocol-specified analysis was to evaluate the relative efficacy of ravulizumab and eculizumab in adult patients with PNH based upon baseline hemolysis level, transfusion history, and demographics.Methods: In this phase 3, randomized, open-label, noninferiority, multicenter study (NCT02946463), patients ≥18 years of age with confirmed diagnosis of PNH, naive to complement inhibitor therapy, with lactate dehydrogenase (LDH) level ≥1.5 times upper limit of normal (xULN), and ≥1 PNH-related sign/symptom at screening received ravulizumab or eculizumab over a 183 day study period. Coprimary efficacy endpoints were transfusion avoidance and LDH normalization. Secondary endpoints were percent change in LDH, change in Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue score, proportion of patients with breakthrough hemolysis, and proportion with stabilized hemoglobin levels. Subgroup analyses were performed on each of these endpoints, based on transfusion history (0, 1-14, or >14 units of packed red blood cells [pRBCs] in the year prior to the first dose of study drug), screening LDH levels (1.5-<3 or ≥3 xULN), sex, age, race, and geographical region. Descriptive statistics are provided with no formal hypothesis testing performed.Results: In total, 246 patients from countries across the Asia-Pacific region (n=124), Europe (n=91), North America (n=9), and South America (n=22) were randomized to ravulizumab (n=125) or eculizumab (n=121). For transfusion avoidance, the point estimates for 15/17 subgroups favored ravulizumab. The treatment effect favored ravulizumab irrespective of prior pRBC transfusion history and baseline LDH levels, as well as nearly all other demographic subgroups assessed (Panel A). With respect to LDH normalization, the point estimates for 11/17 subgroups favored ravulizumab. The treatment effect numerically favored ravulizumab among patients who received 1-14 and >14 pRBCs in the 12 months before randomization, both baseline LDH subgroups, and most of the demographic subgroups (Panel B). No sensitive subgroups were identified for either of the coprimary endpoints. Similarly, point estimates favored ravulizumab in the majority of patient subgroups across each of the key secondary endpoints, including: 8/17 of the subgroups on the assessment of percent change in LDH; 12/17 subgroups on the assessment of change in FACIT-Fatigue score; 13/17 subgroups on the assessment of breakthrough hemolysis; and 13/17 subgroups on the assessment of hemoglobin stabilization.Conclusions: Results of this prespecified analysis revealed point estimates favoring ravulizumab for the majority of the diverse subgroups of PNH patients analyzed. The consistency of these data across subgroups confirms the robustness of the results of this study. The benefit of ravulizumab in terms of transfusion avoidance and LDH normalization was retained across all subgroups. These results provide evidence supporting the use of ravulizumab for the treatment of complement inhibitor-naive patients with PNH regardless of transfusion history, baseline hemolysis level, sex, age, race, or geographic region. DisclosuresWeitz:Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria. Kulagin:Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria. Nakao:Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria; Novartis: Honoraria; Kyowa Hakko Kirin Co., Ltd.: Honoraria. Szer:Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria, Other: Travel Support , Research Funding. Rottinghaus:Alexion Pharmaceuticals, Inc.: Employment, Equity Ownership. Volles:Alexion Pharmaceuticals, Inc.: Employment, Equity Ownership. Damokosh:Alexion Pharmaceuticals, Inc.: Employment, Equity Ownership. Aguzzi:Alexion Pharmaceuticals, Inc.: Employment, Equity Ownership. Larratt:Alexion Pharmaceuticals, Inc.: Honoraria, Research Funding. Risitano:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Alnylam Pharmaceuticals, Inc.: Consultancy, Honoraria, Research Funding; Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Ra Pharmaceuticals, Inc.: Consultancy, Honoraria, Research Funding; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer Inc.: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amyndas Pharmaceuticals: Consultancy.

Outcomes for Initial Patient Cohorts with up to 33 Months of Follow-up in the Hgb-206 Phase 1 Trial

Outcomes for Initial Patient Cohorts with up to 33 Months of Follow-up in the Hgb-206 Phase 1 Trial

A Prospective Analysis of Breakthrough Hemolysis in 2 Phase 3 Randomized Studies of Ravulizumab (ALXN1210) Versus Eculizumab in Adults with Paroxysmal Nocturnal Hemoglobinuria

A Prospective Analysis of Breakthrough Hemolysis in 2 Phase 3 Randomized Studies of Ravulizumab (ALXN1210) Versus Eculizumab in Adults with Paroxysmal Nocturnal Hemoglobinuria

Ravulizumab (ALXN1210) in patients with paroxysmal nocturnal hemoglobinuria: results of 2 phase 1b/2 studies

AbstractRavulizumab (ALXN1210), a humanized monoclonal antibody to complement component C5, was engineered from eculizumab to have a substantially longer terminal half-life, permitting longer dosing intervals for paroxysmal nocturnal hemoglobinuria (PNH) treatment. Two phase 1b/2 multicenter open-label studies evaluated efficacy and safety of multiple doses and regimens of ravulizumab in PNH patients naive to complement-inhibitor treatment. Patients in study 103 (n = 13) received ravulizumab 900 mg (lower trough exposure) or 1800 mg every 4 weeks (higher trough exposure); those in study 201 (n = 26) received 1000 mg every 4, 1600 mg every 6, 2400 mg every 8, or 5400 mg every 12 weeks. Trough exposure levels with study 201 dosing regimens were similar to the study 103 900-mg every-4-weeks regimen. Rapid sustained reduction of plasma lactate dehydrogenase (LDH) occurred across all cohorts (73%-90% at end point vs baseline). A greater proportion of patients had normalized LDH (<234 U/L) at least once from days 29 to 253 in the higher- (85.7%) vs lower-trough-exposure (50.0%-83.3%) cohorts; the weighted average of the proportion of instances of LDH normalization from days 29 to 253 was highest in higher- vs lower-trough-exposure cohorts (62.3% vs 31.4%-54.5%). No patients in the higher-trough-exposure cohort, but 1 to 2 patients in all lower-trough-exposure cohorts, experienced breakthrough hemolysis. Ravulizumab improved quality of life (QoL) measures in all cohorts. Two patients experienced meningococcal infections; both recovered and continued in the study. In summary, ravulizumab provided rapid and sustained reduction in complement-mediated hemolysis and improved QoL at dosing intervals up to 12 weeks. This trial was registered at www.clinicaltrials.gov as #NCT02598583 (study 103) and NCT02605993 (study 201).